2. Lecture Outline
Hypertension
Definition, classification
Prevalence
Complications
Contributing factors
Update on VIIth report of the JNC
Drugs that lower blood pressure
3. Blood Pressure Classification
Classification SBP (mmHg) DBP (mmHg)
______________________________________________________
Normal <120 and <80
Prehypertension 120–139 or 80–89
Hypertension >140/90
Stage 1 Hypertension 140–159 or 90–99
Stage 2 Hypertension >160 or >100
_____________________________________________
4. Essential Hypertension
In 90–95% of cases the cause isn't
known = ESSENTIAL HYPERTENSION
Symptomatic treatment, i.e. reduce
blood pressure. No real cure yet.
5. Identifiable Causes of
Secondary Hypertension
Sleep apnea
Drug-induced or related causes
Chronic kidney disease
Primary aldosteronism
Renovascular disease
Chronic steroid therapy and Cushing’s
syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease
6. Prevalence
High in this country: 50% of adults,
60% of whites, 71% of African
Americans, 61% Mexican Americans
over the age of 60
More prevalent in men than in
women
Highest prevalence in elderly
African-American females
10. National Heart Lung Blood Institute
National High Blood Pressure
Education Program
The Seventh Report of the Joint
National Committee on Prevention,
Detection, Evaluation, and Treatment
of High Blood Pressure (JNC 7, 2003)
http://www.nhlbi.nih.gov/guidelines/hypertension
/index.htm
11. Why Guidelines for
Hypertension?
50 million people with hypertension
in USA 10 years ago – 1:4 overall
(Currently 31 %), half of people > age
60
Only 1 in 2 on drug treatment
to lower BP
Only 1 in 4 age 18-74 controlled to
<140/<90 in USA
12.
13. New BP Goals
<140/<90 and lower if tolerated
<130/<80 in diabetics
<130/<85 in cardiac failure
<130/<85 in renal failure
<125/<75 in renal failure with
proteinuria>1.0 g/24 hours
14. Highlights of Current
Guidelines
JNC, WHO/ISH, BHS,
Canada, and More
New aggressive treatment
strategies based on a patient’s
medical profile
Treat to goal and hit the target,
not to be satisfied with less
15. Treatment Overview
Goals of therapy
Lifestyle modification
Pharmacologic treatment
Algorithm for treatment of
hypertension
Classification and management of
BP for adults
Follow-up and monitoring
17. DASH Diet
Dietary
Approaches
to
Stop
Hypertension
• Emphasizes: Fruits,
vegetables, low fat dairy
foods, and reduced
sodium intake
• Includes whole grains,
poultry, fish, nuts
• Reduced amounts of red
meat, sugar, total and
saturated fat, and
cholesterol
Sacks FM et al: NEJM 344;3-10, 2001
18. Algorithm for Treatment of Hypertension
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling
Indications
Lifestyle Modifications
Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Without Compelling
Indications
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
20. Mean Arterial Pressure
MAP = CO
CO = HR X SV
SNS Blood volume
Heart contactility
Venous tone
X PVR
myogenic tone
vascular responsivenes
nervous control
vasoactive metabolites
endothelial factors
circulating hormones
22. Diuretics
Used as initial therapy alone or in combination with
drugs from other groups
Adverse effects: renin secretion due to volume and Na
depletion
Thiazides: chlorothiazide, hydrochorothiazide
Loop Diuretics: furosemide, bumetanide
Potassium sparing diuretics: spironolactone,
triamterene, amiloride
23. About Diuretics
Antihypertensive and Lipid Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT): Diuretics
have been virtually unsurpassed in preventing the
cardiovascular complications of hypertension.
Diuretics enhance the antihypertensive efficacy of
multidrug regimens, can be useful in achieving BP
control, and are more affordable than other anti-
hypertensive agents.
Despite these findings, diuretics remain under-
utilized.
24. Agents that affect
adrenergic function
a) Agents that prevent adrenergic
transmission (reserpine, guanethedine,
guanadrel)
b) Selective alpha-1 adrenergic receptor
blockers (prazosin, terazosin, doxazosin)
c) Beta-adrenergic blocking agents
(propranolol and others)
d) Agents that act on the CNS (methyldopa,
clonidine, guanabenz, guanfacine)
25. a) Agents that prevent adrenergic
transmission: Reserpine
Mechanism: depletes neurotransmitters (NE,
DA, 5HT) in the storage vesicle of the central
and peripheral nerve endings
Main effects: depress SNS function centrally
and peripherally decreased HR, contractility
and PVR
Adverse effects: depression, insomnia,
nightmares, ulcers, diarrhea, abdominal
cramping, nasal stuffiness, orthostatic
hypotension, dry mouth, impotence
Pharmacokinetics: onset is slow and full effect
is seen in weeks
Use: infrequently
26. Mechanism: Depletes the nerve ending of NE
in the periphery
Main effects: decrease in PVR and decrease
in HR → decrease in BP
Adverse effects: Orthostatic hypotension, Na+
and water retention. Other side-effects
similar to reserpine except the CNS effects
Pharmacokinetics: Poorly absorbed from the
G.I. Onset slow (1-2 weeks). Metabolites
excreted in urine
Use: Not used anymore because of severe
side effects
a) Agents that prevent adrenergic
transmission: Guanethedine
27. Mechanism and main effects Similar to
guanethidine
Adverse effects are less than gunethidine:
less orthostatic hypotension, less diarrhea,
less effect on sexual function.
Pharmacokinetics: better absorption, rapid
onset, shorter duration of action than
guanethidine
a) Agents that prevent adrenergic
transmission: Guanadrel
28. b) Selective alpha-1 adrenergic
receptor blockers
(prazosin, terazosin, doxazosin)
They favorably influence plasma lipid profile, and do not
interfere with glucose metabolism.
Mechanism: block α1 receptors in vasculature
Main effects: decreased PVR decrease BP
Adverse effects: 1st dose phenomenon, fluid
retention, dizziness, headache
Pharmacokinetics: t1/2= 4.5, 12, 20,
respectively
Use: used in stage 1 and stage 2 HT in
combination with a diuretic and a β-blocker
31. Propranolol
Mechanism:
Block cardiac β1 receptors lower CO
Block renal β1 receptors lower renin, lower PVR
Main effects: decrease HR and PVR
Adverse effects: bradycardia, depression, β2
blockade in airways, glucose and lipid
metabolism, vasoconstriction in extremities
Pharmacokinetics: GI, 30-50% metabolized in the
first-pass in liver. T1/2: 3-5 hours, Slow- release
propranolol available
Use: used in stage 1 and 2 HT alone or in
combinations with a diuretic and/or vasodilator
Drug Interactions: verapamil, diltiazem, digitalis
(caution AV Block)
32. Labetalol
A combined alpha-1, beta-1, and
beta-2 blocker. Beta blocking
action is more prominent. It also
has some ISA property.
Can be given i.v. for hypertensive
emergencies
33. d) Agents that act on the CNS
(α−methyldopa, clonidine)
Favorable effect: lower PRA
Mechanism: α-me-dopa metabolized to α-me-
norepinephrine, an α-2 agonist, that suppresses
SNS output from the CNS. Others are α-2 agonist
themselves.
Main effects: decreases PVR and HR
Adverse effects: sedation, drowsiness, dry mouth,
impotence, bradycardia, withdrawal syndrome
(rebound HT), false (+) Coombs’ antiglobulin test
Pharmacokinetics: oral or parenteral, transdermal;
T1/2 = 2, 10, 6, 14-17 h, respectively
Use: stage 1 and 2 HT
34. Vasodilator Drugs
Common adverse effects: fall in BP reflex
tachycardia, also fall in BP renin Na/H2O
retention
a) Calcium entry blockers (nifedipine
and others)
b) Potassium channel openers
(minoxidil, diazoxide i.v., pinacidil)
c) Direct acting vasodilators
(hydralazine, Na-nitroprusside i.v.)
35. a) Calcium entry blockers
mechanism: inhibit Ca entry through L-type
voltage gated channels
Non- Dihydropyridines : verapamil,
diltiazem
Dihydropyridines: nifedipine,
nicardapine, amlodipine
36. Nifedipine
Mech: selective blockade of vascular Ca
channels
Main effect: vasodilatation lower PVR
lower BP
Adverse effects: headache, flushing,
nausea, ankle edema, dizziness, reflex
tachycardia with short acting version (now
have Procardia SR)
(no reflex tachycardia with verapamil and
diltiazem)
Use: Hypertension (more effective in African-
Americans), angina. Not useful as an
antiarrhythmic drug
37. Verapamil and Diltiazem
Mechanism: Blockade of Ca channels in the
vasculature, heart muscle and the AV node
Main effects: same as nifedipine group
Adverse effects: Similar to nifedipine except
that they do not cause reflex tahycardia
Drug interactions: Caution for AV block with
beta blockers, and digitalis
Use: Hypertension, angina, arrhythmias
38. b) Potassium channel openers
(minoxidil, diazoxide i.v)
Mechanism: open K-channels of vascular
smooth muscle cells K-efflux
hyperpolarization vasodilatation
Main effect: vasodilation lower PVR
lower BP
Adverse effects: reflex tachycardia, Na and
fluid retention, (minoxidil: hirsutism-
Rogaine. Diazoxide: hyperuricemia,
hyperglycemia –used in hypoglycemia)
Use: Diazoxide i.v. in hypertensive
emergencies
39. c) Direct acting vasodilators
(Na-nitroprusside)
Mechanism: metabolite is nitric oxide
cGMP. NO is a rapid acting venous and
arteriolar vasodilator
Main effect: vasodilation lower PVR
lower BP
Adverse Effects: Reflex tachycardia, severe
hypotension, possible cyanide poisoning
Pharmacokinetics: rapid acting, i.v. drip,
short plasma half-life
Use: Hypertensive emergencies
40. c) Direct acting vasodilators
(hydralazine)
Mechanism: Direct vasodilator of arterioles
Main effect: vasodilation lower PVR
lower BP
Adverse effects: reflex tachycardia, Na
retention, hirsutism, lupus–like syndrome
Pharmacokinetics: oral, slow onset
Use: with a beta blocker and a diuretic
41. Angitensin Converting Enzyme
ACE
Angiotensin I Angiotensin II
ACE
Bradykinin (vasodilator) Inactive peptide
ANGIOTENSIN I ANGIOTENSIN II
ACE
→
ANGIOTENSIN I ANGIOTENSIN II
ACE
→
BRADYKININ (vasodialtor) INACTIVE PEPTIDE
ACE
→
BRADYKININ (vasodialtor) INACTIVE PEPTIDE
ACE
→
42. Agents that affect RAS
a) ACE inhibitors
captopril, enalapril, lisinopril
b) Angiotensin II receptor
blockers (ARB)
losartan, valsartan, irbesartan
43. a) ACE inhibitors
captopril, enalapril, lisinopril, rampiril)
No adverse effects on plasma lipids, glucose, sexual
function. Drug of choice in diabetes-related early stage
proteinuria. Contraindicated in pregnancy. Not as effective in
African-Americans
Mechanism: inhibit ACE low circulating Ang II
decreased PVR
Main effects: decreased PVR decreased BP
Adverse effects: skin rash, taste, cough, hyperkalemia
Pharmacokinetics: T1/2 = 3, 11, 12, respectively
Use: used in stage 1 and 2 HT; also for congestive heart
failure
44. b) Angiotensin II receptor blockers
(ARB) (losartan-Coozar, valsartan-Diovan,
irbesartan-Avapro)
Mechanism: selectively block Ang II AT-1
receptor decrease PVR decrease BP
Adverse effects: No Cough, very few
adverse similar to ACE inhibitors
45. BP ↓
BV ↓
Na+ depletion
NE release
from nerve
ending
RENIN RELEASE
BP ↑
BV ↑
Na+ retention
+ -
Vasoconstriction
Aldosterone
secretion
Angiotensin release
+
+ +
+
+
+
Stimulants for ADH
1) ↓ ECF volume
2) osmolality of plasma
+